Chlorthalidone

Mechanism of Action

Chlorthalidone exerts its therapeutic action by antagonizing sodium-chloride symporter in the distal convoluted tubule of the nephron. This drug is similar to a thiazide diuretic in its mechanism of action, although it has a mildly altered chemical structure. Both thiazide and thiazide-like diuretics contain a sulfonamide group that also works to inhibit carbonic anhydrase and its antagonistic action at the distal convoluted tubule.[11]

Chlorthalidone inhibits sodium reabsorption at the level of the distal convoluted tubule and thus chloride via inhibition of the Na-Cl symporter. By removing sodium reabsorption at this location, the distal convoluted tubule of the nephron retains a higher sodium content. This lack of reabsorption alters the osmotic gradient and shifts fluid distribution from the outside to the inside of the tubule. The increased osmotic load from its elevated sodium concentration leads to elevated intratubular volume, thus promoting its diuretic effect. The increased elimination of sodium and extracellular fluid leads to a reduction in intravascular water and solute concentration. Reduction of the intravascular volume and osmotic gradient decreases hydrostatic pressure, ultimately leading to a clinically significant decrease in blood pressure.

Pharmacokinetics

Absorption: Chlorthalidone typically begins to exert its therapeutic effects within 3 hours of administration, with peak plasma concentrations achieved 2 to 6 hours after the dose.

Distribution: Chlorthalidone exhibits high protein binding, predominantly to albumin, owing to its affinity for erythrocyte carbonic anhydrase.

Metabolism: Chlorthalidone undergoes partial hepatic metabolism.

Excretion: Renal excretion plays a pivotal role in eliminating chlorthalidone from the body, with the major portion excreted unchanged via the kidneys. This drug's elimination half-life ranges from 45 to 60 hours, contributing to its sustained duration of action, which typically lasts between 48 to 72 hours.[14]

Administration

Available Dosage Forms

Chlorthalidone is available solely as an oral medication. The fixed-dose combination of atenolol/chlorthalidone, azilsartan/chlorthalidone, and clonidine/chlorthalidone is also available.[15]

Available Strengths

Chlorthalidone is available in 15 mg, 25 mg, and 50 mg tablets.

Adult Dosage

Dosing regimens vary depending on clinical indication. For the treatment of heart failure, guidelines recommend starting at 12.5 mg or 25 mg daily and titrating up to 100 mg daily as necessary. For generalized edema, dosing begins with 50 to 100 mg daily and can be titrated to a maximum of 200 mg daily. As outlined below, chlorthalidone can also be utilized to manage calcium nephrolithiasis, which is generalized administered at 25 mg daily.

Hypertension: starting dose of 12.5 to 25 mg daily, maximum dose of 100 mg daily (ACC/AHA) [16]

Heart failure: starting dose of 12.5 mg or 25 mg daily, maximum dose of 100 mg daily (ACC/AHA/HFSA) [17]

Generalized edema: starting dose of 12.5 to 25 mg orally once to twice daily, maximum dose of 100 mg daily (ACC Expert Consensus)[18]

Calcium nephrolithiasis (off-label): 25 mg daily

Specific Patient Populations

Hepatic impairment: No dosage adjustments for chlorthalidone are provided in the product labeling; use caution. 

Renal impairment: According to the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines, thiazide diuretics lose efficacy in diuresis and lower blood pressure as the glomerular filtration rate (GFR) worsens. However, chlorthalidone remains effective at a GFR <30 mL/min/1.73 m².[19] In a double-blind, randomized, placebo-controlled trial among patients with stage 4 chronic kidney disease (eGFR 15 to 30 mL/min/1.73 m²) and uncontrolled hypertension, chlorthalidone therapy significantly improved blood pressure control compared to placebo at 12 weeks.[20]

Pregnancy considerations: There is insufficient research to check teratogenicity, but chlorthalidone should be used only during pregnancy if absolutely necessary. Observational studies suggest that chlorthalidone use in pregnancy does not significantly increase the risk of major congenital disabilities or miscarriage. However, thiazide diuretics, including chlorthalidone, have been associated with adverse fetal outcomes such as jaundice, thrombocytopenia, hypoglycemia, and electrolyte imbalances. Consequently, chlorthalidone is not the preferred first-line treatment for hypertension in pregnancy. While chlorthalidone/thiazides do not prevent or alter the course of pre-eclampsia, they should not be the primary therapy for hypertension during pregnancy.

Breastfeeding considerations: The concentration of chlorthalidone in breast milk is relatively low; however, the drug's prolonged clearance kinetics can result in its accumulation in newborns, particularly in premature infants. Additionally, chlorthalidone's pharmacological properties may inhibit lactation. Therefore, an alternative medication may be considered to minimize potential risks associated with infant exposure to chlorthalidone via breast milk.[21]

Pediatric patients: The safety and efficacy of chlorthalidone in pediatric populations have not been conclusively established. As per the American Academy of Pediatrics (AAP), the initial recommended dose of chlorthalidone is 0.3 mg/kg, with a maximum daily dose of 2 mg/kg (or 50 mg per day).[22]

Older patients: The patient's age is also a consideration when determining the appropriate chlorthalidone dosage. Lower initial doses, typically ranging from 6.25 mg to 12.5 mg daily, are recommended, with gradual titration as needed. Diuretic medications, such as chlorthalidone, a Beers criteria medication, should be used cautiously.[23]

Adverse Effects

Significant adverse effects are electrolyte derangement (hypokalemia, hyponatremia, etc), hypersensitivity reaction, and precipitation of acute gout attacks. The adverse effects of chlorthalidone involve most organ systems to differing degrees and manifestations. Of significance, electrolyte derangement is a commonly reported adverse effect of this medication, which results from increased diuresis and altering of nephron physiology. Most commonly, chlorthalidone causes hypokalemia, but it may also cause hyponatremia or hypochloremia. These known derangements make monitoring serum electrolytes essential for patients receiving chlorthalidone periodically throughout hypertensive management. 

Reported Adverse Effects (per the Food and Drug Administration):

• Gastrointestinal adverse effects: anorexia, gastritis, nausea, emesis, cramping, loose stools, constipation, and pancreatitis [24]
• Neurologic reactions: paresthesias, dizziness, and headaches
• Hematologic reactions: aplastic anemia, leukopenia, agranulocytosis, and thrombocytopenia
• Cardiovascular reaction: orthostatic hypotension
• Dermatologic reactions: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (cutaneous vasculitis), Lyell syndrome (toxic epidermal necrolysis), pseudoporphyria [25]
• Other adverse reactions include hyperglycemia, glycosuria, muscle spasm, weakness, restlessness, impotence, and hyperuricemia.[26]

Drug-Drug Interactions

• Digitalis: Medications like digitalis can influence serum electrolyte levels, potentially leading to warning signs such as dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, low blood pressure, decreased urine output, rapid heart rate, and gastrointestinal issues like nausea and vomiting.
• Insulin and oral hypoglycemic agents: Chlorthalidone therapy may affect insulin needs in patients with diabetes, potentially necessitating adjustments in insulin dosage or requirements for higher doses of oral hypoglycemic agents. Additionally, latent diabetes may become apparent during treatment with chlorthalidone.
• Tubocurarine: Chlorthalidone and similar drugs can increase sensitivity to tubocurarine, affecting its action.
• Norepinephrine: Chlorthalidone may diminish arteries' responsiveness to norepinephrine, although the effect is not significant enough to render norepinephrine ineffective for therapeutic use.
• Lithium: Close monitoring of lithium levels is imperative in individuals undergoing lithium treatment due to the potential of diuretics such as chlorthalidone to diminish lithium excretion, consequently triggering lithium toxicity.[27]

Contraindications

Absolute Contraindications

• Hypersensitivity to chlorthalidone
• Hypersensitivity to the sulfonamides-derived medications
• Anuria

Warning and Precautions

• Advanced chronic kidney disease
• Significant electrolyte derangement (severe hypokalemia, severe hyponatremia)
• Orthostatic hypotension
• Syncope
• Older adult population (due to risk of hyponatremia)
• Pregnancy
• Hypercalcemia
• Severe hyperuricemia or gout [26]

A recent study investigated the effects of potassium magnesium citrate (KMgCit) versus potassium chloride (KCl) supplementation during chlorthalidone therapy for hypertension. The primary goal of this study was to evaluate changes in metabolic parameters. The study found that chlorthalidone alone increased fasting plasma glucose levels and reduced serum potassium, magnesium, and urinary citrate excretion. However, supplementation with KMgCit attenuated the rise in fasting plasma glucose compared to KCl. These findings suggest that KMgCit may be more effective than KCl in preventing chlorthalidone-induced hyperglycemia, potentially enhancing tolerability and cardiovascular safety.[28]

Monitoring

The following items require periodic monitoring when the patients take chlorthalidone. 

• Serum electrolytes: Serum sodium, potassium, chloride, and calcium levels should be monitored.[29] 
• Fluid status and blood pressure: All patients taking chlorthalidone require observation for dryness of mouth, thirst, lethargy, hypotension, oliguria, tachycardia, palpitations, and gastrointestinal disturbances, such as nausea and vomiting. Chlorthalidone is a diuretic, so an inappropriately high dose can cause severe volume depletion.
• Magnesium level: It can increase the urinary excretion of magnesium and may result in hypomagnesemia.
• Uric acid level: Hyperuricemia may occur, or frank gout may be precipitated in certain patients receiving chlorthalidone.
• Serum glucose level: Serum glucose may increase with chronic use. 

There is insufficient research on teratogenicity, but chlorthalidone should be used during pregnancy only if necessary.

Toxicity

Signs and Symptoms of Overdose

• Nausea
• Weakness
• Dizziness due to severe hypotension
• Electrolyte disturbances such as hypokalemia, hyponatremia, and hypomagnesemia

Management of acute overdosage

• No specific antidote is available
• Gastric lavage
• Supportive management includes intravenous dextrose or normal saline for hypotension and intravenous potassium chloride for severe hypokalemia.

Enhancing Healthcare Team Outcomes

As a sulfonamide-derived medication, the clinician must review relevant allergies when prescribing chlorthalidone. An interprofessional team approach, including clinicians (MDs, DOs, NPs, PAs), specialists, nurse practitioners, physician assistants, nurses, and pharmacists, can help to maintain updated allergies. A review of allergies can start upon reception by asking patients to review their previous chart and update relevant sections, including allergies. While in a hospital setting, it can be prompted before administration by the clinician. In a pharmacy setting, the pharmacist can inquire before dispensing chlorthalidone. Additionally, EMR software now allows an additional barrier with risk-advisory when prescribing medication to which patients are allergic.[30] 

In addition to allergies, clinicians and pharmacists are responsible for counseling the patient, verifying dosing, and monitoring for adverse events. Pharmacists must also perform medication reconciliation to preclude any possible drug-drug interactions and notify the other interprofessional healthcare team members when concerns arise.

Updating the type of adverse reaction occurring with the allergy is vital to avoid and characterize the true allergy. Deciphering whether a true allergy or previous adverse effects from a medication is crucial as it changes therapeutic options for the patient.[30] The interprofessional paradigm contributes to positive patient outcomes when using chlorthalidone.